Receptors for the Fc portions of immunoglobulins are important in triggering many of the protective functions of monocytes, macrophages and polymorphonuclear cells. Receptors for IgG (Fcγ receptors or FcγR) on these cells have been extensively investigated and monoclonal antibodies against these receptors have been generated and shown to be therapeutically effective (See e.g. European Patent No. 255 249 entitled “Monoclonal Antibodies to Fc Receptor for Immunoglobulin G on Human Mononuclear Phagocytes”).
IgA receptors (Fcα receptor or CD89) are also capable of promoting effector cell function. Binding of ligand to CD89 triggers phagocytosis and antibody mediated cell cytotoxicity in leukocytes and CD89-bearing cell lines. CD89 can also cooperate with receptors for IgG on effector cells in enhancing the phagocytosis of target cells.
CD89 is a receptor which binds to the Fc portion of IgA, the most abundant Ig in the human body (Kerr, M. A. 1990, Biochem. J. 271:285–296). CD89 is constitutively expressed primarily on cytotoxic immune effector cells including polymorphonuclear leukocytes (PMN), monocytes, macrophages, neutrophils and eosinophils. (Morton, H. C., et al., 1996 Critical Reviews in Immunology 16:423). CD89 expression on a sub-population of lymphocytes (Morton, H. C., et al., 1996 Critical Reviews in Immunology 16:423), and on glomerular mesangial cells also has been reported (Gomez-Guerrero, C., et al., 1996 J. Immunol. 156:4369–4376). Moreover, CD89 expression on monocytes and PMN can be enhanced by TNF-α (Gesl, A., et al., 1994 Scad. J. Immunol. 39:151–156; Hostoffer, R. W., et al., 1994, The J. Infectious Diseases 170:82–87), IL-1, GM-CSF, LPS or phorbol esters (Shen L., et al., J. Immunol. 152:4080–4086; Schiller, C. A. et al., 1994, Immunology, 81:598–604), whereas IFN-γ and TGF-β1 decrease FcαRI expression (Reterink, T. J. F., et al., 1996, Clin. Exp. Immunol. 103:161–166).
The α-chain of human CD89 is a heavily glycosylated, type one transmembrane molecule belonging to the Ig super-gene family which also includes receptors for IgG and IgE. One gene located on chromosome 19 encodes several alternatively spliced isoforms of the FcαRI alpha chain (55–110 kDa; Morton, H. C., et al., 1996 Critical Reviews in Immunology 16:423). Myelocytic CD89 has been shown to be associated with the FcR γ-chain which is implicated as playing a role in CD89 signal transduction (Morton, H. C. et al. 1995, J. Biol. Chem. 270:29781; Pfefferkorn, L. C., et al. 1995, J. Immunol., 153:3228–3236, Saito, K. et al., 1995, J. Allergy Clin. Immunol. 96:1152).
CD89 binds both antigen-complexed and monomeric IgA1 and IgA2 (Mazangera, R. L. et al., 1990 Biochem. J. 272:159–165), consistent with the receptor being saturated in vivo with monomeric IgA in the same manner as FcγR and FcεRI are saturated with IgG and IgE respectively. Cross-linking CD89 on myeloid effector cells, by polymeric IgA, IgA immune complexes, or mAb specific for epitopes within or outside the ligand binding domain, stimulates degranulation, superoxide release, secretion of inflammatory cytokines, endocytosis and phagocytosis (Patty, C., A. Herbelin, A. Lihuen, J. F. Bach, and R. C. Monteiro. 1995 Immunology. 86:1–5; Stewart, W. W., R. L. Maz Yegera, L. Shen, and M. A. Kerr. 1994 J. Leucocyte Biology. 56:481–487; Stewart, W. W., and M. A. Kerr. 1990. Immunology. 71:328–334; Shen, L. 1992. J. Leukocyte Biology. 51:373–378.). These physiological responses triggered via CD89 can be important in the first line of humoral defense on mucosal surfaces (Morton, H. C., M. van Egmond, and J. G. J. van de Winkel. 1996 Critical Reviews in Immunology. 16:423).